The gut incretin hormones, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are responsible for >50% of nutrient stimulated insulin release and have roles in β-cell glucose competence, stimulating β-cell growth, differentiation, proliferation and cell survival. On release, these hormones are rapidly inactivated (GLP-1; t1/2=1.5 min) by a ubiquitous serine protease, dipeptidyl peptidase IV (DPP-IV) which acts by specifically cleaving Pro or Ala terminal amino acid residues. Inhibition of DPP-IV has been shown to extend the half-life of GLP-1 with favorable effects on stimulation of insulin secretion, inhibition of glucagon release and slowing gastric emptying.
DPP-IV inhibition, through the preservation of active GLP-1 levels, has the potential to slow or even prevent the progression of type 2 diabetes by stimulating insulin gene expression and biosynthesis, increasing the expression of the β-cell's glucose-sensing mechanism and promoting genes involved in the differentiation of β-cells. As the glucose lowering effects of GLP-1 are dependent on elevated blood glucose and subside as glucose levels return to normal, the probability of hypoglycemia during treatment with a DPP-IV inhibitor is expected to be very low. Indeed; studies on the long term inhibition of DPP-IV and with DPP-IV knock-out mice have shown no adverse effects.
Application of DPP-IV inhibitors delays the inactivation of GIP and GLP-1 thereby allowing increased insulin secretion and improved blood glucose control. It could be shown in animal models and diabetic patients that the overall blood sugar control of the body is improved due to a restoration of proper insulin secretion and action. Such a mode of action is unique to this therapeutic principle. The above studies suggest the possibility of long term safe treatment of type-2 diabetes with DPP-IV inhibitors.